MOLECULAR MECHANISMS OF ANGIOTENSIN-II IN MODULATING CARDIAC-FUNCTION- INTRACARDIAC EFFECTS AND SIGNAL-TRANSDUCTION PATHWAYS

Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system (RAS), regulates volume and electrolyte homeostasis and is inv olved in cardiac and vascular cellular growth in humans and other spec ies, This system, which has been conserved throughout evolution, plays an important role in cardiac and vascular pathology associated with h ypertension, coronary heart disease, myocarditis and congestive heart failure. The traditional RAS is viewed as a system in which circulatin g Ang II is delivered to target organs and cells. However, in the past decade, a local RAS has been described in cardiac cells, providing ev idence for autocrine and paracrine pathways by which biological action s of Ang II could be mediated. The critical actions of Ang II are medi ated primarily through the AT(1), G-protein (guanylyl nucleotide bindi ng protein) coupled receptor. In addition to coupling to conventional G-protein signal transduction pathways, the AT(1) receptor was recentl y shown to increase the tyrosine phosphorylation of several intracellu lar substrates, including the STAT (Signal Transducers and Activators of Transcription) family of novel transcription factors, in rat cardia c fibroblasts, myocytes and vascular smooth muscle cells, and AT(1) re ceptor transfected CHO cells. It has been shown that Ang II stimulates the tyrosine phosphorylation and nuclear translocation of Stat1 (Stat 91) and Stat3 (Stat 92). Angiotensin II acting directly through the A T(1) receptor, induces the formation of a complex of STAT proteins ter med SIF (sis-inducing factor) which binds the DNA sequence, SIF (sis-i nducing element) present in the promotor element of many genes. This p rovides evidence for a direct role of Ang II in mediating inflammatory and remodeling responses through the JAK-STAT pathway. Thus, it is li kely that the JAK-STAT pathway has an important role in Ang II-mediate d effects on gene transcription, cardiac and vascular cellular growth/ development, and inflammatory responses. (C) 1997 Academic Press Limit ed.